Nerve growth factor (NGF) was shown to be critical for the survival of control and trisomy 21 (Ts21 Down syndrome) human fetal dorsal root ganglion (DRG) neurons in culture. DRG neurons grown in the absence of NGF displayed prolonged action potentials with a slower rate of depolarization. Replating was essential for accurate determination of fast neuronal currents. Cultured hippocampal neurons from fetal mouse trisomy 16 (Ts21), a model for Down syndrome, showed no significant abnormality in the action potential, or in the voltage dependence of responses to N-methyl-D- aspartate (NMDA). Calcium gated currents were abnormal were abnormal. Fluorescence studies of catecholamines suggested that fetal mouse trisomy 16 neurons have abnormal neurotransmitter uptake. The hippocampus and cerebellum, but not the cerebral hemispheres of mouse trisomy 16 fetal brain have a reduced ability to release prostaglandin D2, suggesting abnormal arachidonate metabolism.